5-(2-methylene-acyl)-benzofuran-2-carboxylic acids and pharmaceutically acceptable salts thereof

ABSTRACT

5-(2-Methylene-acyl)-benzofuran-2-carboxylic acids, 5-(2methylene-acyl)-benzothiophene-2-carboxylic acids and pharmaceutically acceptable salts thereof with bases, which compounds have valuable simultaneous diuretic and saluretic activity, therapeutic compositions containing such compounds or their pharmaceutically acceptable salts with bases as well as a method for producing simultaneous diuretic and saluretic effects in mammals. An illustrative embodiment is 5-(2-methylenebutyryl)-6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid.

United States Patent [191 Habicht et al.

[ Sept. 25, 1973 5-(Z-METHYLENE-ACYL)-BENZOFURAN-2- CARBOXYLIC ACIDS AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF [75] Inventors: Ernst Habicht, Oberwil/Basel,

Switzerland; Bernard Libis, Saint-Louis, France [73] Assignee: Ciba-Geigy Corporation, Ardsley,

221 Filed: Nov. 5, 1970 [21] Appl. No.: 87,339

Related U.S. Application Data [63] Continuation-impart of Ser. No. 827,883. May 26,

l969, abandoned.

[30] Foreign Application Priority Data May 30, 1968 Switzerland 8032/68 Nov. 20, I969 Switzerland l7272/69 [52] US. Cl. 260/3462 R, 424/285, 260/330.5, 424/275 [51] Int. Cl C07d 5/36 [58] Field of Search 260/3462 R [56] References Cited OTHER PUBLICATIONS Zergenyi et al., Chem. Abstr., Vol. 71, 1969), 81 144rof S. African 6804836, January 27, 1969.

Primary ExaminerAlex Maze] Assistant ExaminerBernard Dentz Att0rneyKarl F. Jorda and Bruce M. Collins [57] ABSTRACT V 5-(2-Methylene-acyl)-benzofuran-2-carboxylic acids, 5-( 2-methylene-acyl)-benzothiophene-2-carboxylic acids and pharmaceutically acceptable salts thereof with bases, which compounds have valuable simultaneous diuretic and saluretic activity, therapeutic compositions containing such compounds or their pharmaceutically acceptable salts with bases as well as a method for producing simultaneous diuretic and saluretic effects in mammals. An illustrative embodiment is 5-(2-methylene-butyryl)-6-methyl-2,3-dihydrobenzofuran-Z-carboxylic acid.

9 Claims, No Drawings 1 -(2-METHYLENE-ACYL)-BENZOFURAN-2- CARBOXYLIC ACIDS AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF This application is a continuation in part of Ser; No. 827,883, filed 5/26/69, now abandoned.

DETAILED DISCLOSURE The present invention relates to new heterocyclic carboxylic acids having valuable pharmacological properties. More especially, the present invention relates to new 5-(2-methyleneacyl)-benzofuran-2- carboxylic acids, 5-(2-methylene-acyl)- benzothiophene-2-carboxylic acids and pharmaceutically acceptable salts thereof with bases which compounds exhibit simultaneous diuretic and saluretic activities. In a further aspect the present invention provides therapeutic compositions consisting essentially of (l) a compound of pharmaceutically acceptable salt thereof with a base as aforesaid and (2) a pharmaceutical carrier therefor. The invention also provides a method for producing a simultaneous diuretic and saluretic effect in a mammal which comprises administering to said mammal an effective amount of a compound according to the instant invention or a pharmaceutically acceptable salt thereof with a base.

in accordance with the foregoing the present invention provides, in its broadest aspect, a compound of the formula I wherein R is alkyl having at most six carbon atoms,

X is oxygen or sulfur,

Y, and Y, are hydrogen or ethyl, and

Z, and Z, are hydrogen, chloro, fluoro, bromo,

methyl, ethyl, methoxy or ethoxy as well as the pharmaceutically acceptable salts thereof with bases.

in the above compounds, and in the starting materials referred to below Z, occupies the 4- or 6- position and Z, occupies the 6- or 7- position. R is, for example, the methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, amyl or hexyl group.

A preferred sub-class of compounds according to the instant invention are those having the formula I wherein R is alkyl having at most 6 carbon atoms,

X is oxygen,

Y, and Y, are hydrogen,

Z, is hydrogen or methyl and Z, is methyl, chloro or fluoro,

as well as the pharmaceutically acceptable salts thereof with bases.

Especially preferred compounds of the formula I are 2,3-dihydro-5-(2-methylene-valeryl)-6,7-dimethyl' benzofuran-Z-car-boxylic acid 2,3-dihydro-5-(2- methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid, 2,3-dihydro-5-(Z-methylene-butyryl)-6chlorobenzofuran-Z-carboxylic acid, 2,3-dihydro-5-(2- methylene-3-methyl-butyryl)-6-methyl-benzofuran-2- 2 carboxylic acid, 2,3-dihydro-5-(2-methylene-butyryl)- 6-fluoro-benzofuran-2-carboxylic acid, 2,3-dihydro-5- (2-methylene-butyryl)-6,7-dimethyl-benzofuran-2- carboxylic acid and 2,3-dihydro-5(2-methylene- 5 propionyl-6-methyl-benzofuran-Z-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.

Compounds of the formula I are produced, according to a first process, by decomposing a compound of the 10 formula II H Am (Ill) Suitable starting materials of the formula II are, e.g.

such compounds for which the radicals R, X, Y,, Y Z and Z conform to those listed under formula I. These starting materials are produced, for example, as follows: starting with carboxylic acids of the formula IV, which are starting materials for a second process described below, these compounds are condensed, according to the Friedel-crafts reaction, with the aid of aluminum chloride in carbon disulfide with carboxylic acid chlorides of the formula Na R CH, COCI (IVa) wherein R has the meaning given under formula I, to

form compounds of the formula IVb Z COOH (IVb) wherein R, X, Y, Y,, Z, and 2; have the meanings given under formula I. The obtained reaction products are subsequently converted, by means of formaldehyde or paraformaldehyde and a secondary organic base,

wherein X, Y Y Z and Z have the meanings given under formula 1, with a carboxylic acid halide of the formula V,

or with a carboxylic acid anhydride of the formula VI wherein R has the meaning given under formula 1, and Q is halogen,

and, optionally, converting the reaction product into a salt.

Q is preferably chlorine or bromine. Suitable catalysts for the reaction according to Friedel-Crafts are, e.g. aluminum chloride and tin(lV)-chloride, also zinc chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid. The stated acids are preferentially used where the acylation agent is a carboxylic acid anhydride. The reaction is preferably performed in a solvent. Suitable solvents are, e.g. aliphatic or cycloaliphatic hydrocarbons such as heptane or cyclohexane, nitrohydrocarbons such as nitromethane, nitrocyclohexane or nitrobenzene, or halogen hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride, dichlorobenzene and, moreover, carbon disulfide.

Suitable starting materials of the formula IV, wherein X is an oxygen atom, are, e.g. compounds of which the radicals Y,, Y, Z, and Z, conform to the groups listed under formula 1. Of these types of compounds, the 2,3- dihydrobenzo-furan-2-carboxylic acid [cp. R. Fitting and G. Ebert, Ann, Chem- 216, 116 (1883)]and 2,3- dihydro-6-methoxy-benzofuran-2-carboxy-lic acid [cp. W. Will and P. Beck, Chem. Ber. 19, 1793 (1886)]are, for example, known. Further compounds of this series, e.g. starting with substituted 2-a1lyl phenols, can be produced as follows: The substituted 2-allyl phenols are oxidised with peracetic acid to the corresponding 2-(2,3-epoxypropyl)-phenols and these are rearranged by heating into the corresponding 2,3-dihydro-2- hydroxymethyl benzofurans, which are oxidised with potassium permanganate to corresponding 2,3- dihydrobenzo-furan-2-carboxylic acids. For example, the 2,3-dihydro-6-chlorobenzofuran'2-carboxylic acid is produced by this process, starting with the 2-allyl-5- chlorophenol and by way of the intermediate products 2-(2,3-epoxypropyl)-5-chlorophenol and 2,3-dihydro- 2hydroxymethyl-6-chloro-benzofuran. Moreover, compounds of the formula IV can also be obtained by reducing optionally substituted benzofuran-Z-carboxylic acids, e.g. with sodium amalgam, to obtain corresponding 2,3-dihydro-benzofuran- Z-carboxylic acids. For example, the 2,3-dihydro--methylbenzofuran-2 -carboxylic acid is produced according to this process, starting with the 6-methylbenzofuran-2carboxylic acid [cp. K. von Auwers, Ann. Chem. 408, 255 (1955)].

Starting materials of the formula 11 wherein X is sulfur are produced by an analogous manner by reduction of the corresponding substituted benzo [b]thiophene- 2-carboxylic acid with sodium amalgam. Some of the benzo [b]thiophene-2-carboxylic acids necessary as starting material, are already known, e.g. the 6-methylbenzo[b]thiophene-2-carboxylic acid [cp. Y. Matsuki, T. Kanda, Nippon Kagaku Zazshi, 86, 99-102 (1965)] and the others can be obtained in an analogous manner, for example by acylating the corresponding substituted benzo[b]thiophene. Also can be obtained substituted benzo[b]thiophene-2-carboxylic acids by condensation of o-halogen benzene aldehydes to form the corresponding substituted 5-(o-halogen-benzyliden)- rhodanine and boiling these with sodium hydroxide and if necessary heating with sodium methylate in dimethylene glycol at about -160 (cp. M.D. Castle, R.G. Plevey and Y.C. Tatlow, J. Chem. Soc. 1968, 1225-1277).

According to a third process, compounds of the formula I are produced by dehalogenating a compound of the formula VI] Z3 (VII) wherein R, X, Y Y Z and Z have the meanings given under formula I, and

Q is halogen,

and, optionally, converting the reaction product into a salt.

Q is preferably chlorine or bromine. Dehalogenation can be performed with the aid of metals such as, e.g. copper, magnesium, aluminum, iron, and in particular, by means of zinc dust. Since dehalogenation is, in general, a pronounced exothermic reaction, it is advantageously carried out in a solvent. If zinc dust is used as a dehalogenating agent, then suitable solvents are, e.g. lower alkanols, such as methanol or ethanol. Also suitable, apart from metallic dehalogenating agents, are non-metallic ones, e.g. alkali metal iodides. Examples of these are sodium or potassium iodide, which are likewise preferably used in a solvent. Suitable solvents are, e.g. lower alkanols such as methanol or ethanol, or lower alkanons such as acetone or methylethyl ketone.

As starting materials of the formula Vll, those compounds can, for example, be used, of which the groups Q, R, X, Y Y Z and Z conform to the groups listed under formulae 1 and VII. Such compounds are obtained, for example, starting with carboxylic acids of the formula N, which are starting materials for the secnd process. These carboxylic acids can be acylated in -position, e.g. according to the Friedel-Crafts reaction using aluminum chloride in nitrobenzene, with carboxylic acid chlorides of the formula Vlla wherein R has the meaning given above under formula I and Q is preferably chloro or bromo.

It has now been found that the compounds of formula I possess valuable pharmacological properties in conjunction with a high therapeutic index. In particular, they exhibit a simultaneous diuretic and saluretic activity which may be determined in various standard tests with experimental animals [cp. E.G. Stenger et al, Schweiz. Med. Wochenschr. 89, 1126 (1959)] These properties characterise the new compounds as being suitable for the treatment of disturbances caused by insufficient excretion of electrolytes, especially of sodium chloride. Such disturbances are the cause of oedema and hypertension. Thus it was found that 5-(2- methylene-butyryl)-6-methyl-2,3- dihydro-benzofuran- 2-carboxylic acid, in a dosage of 5 mg/kg per os in the case of the dog, increases the excretion of sodium chloride ions and the excretion of urine to a marked degree whereas the excretion of potassium ions is increased to only a minor extent.

A similar effect is demonstrated employing 2,3- dihydro-5-(2-methylene-valeryl)-6,7-dimethylbenzofuran-2-carboxylic acid, 2,3-dihydro-5-(2- methylene-butyryl)-6-chloro-benzofuran-2-carboxylic acid, 2,3-dihydro-5-(2-methylene-3-methyl-butyryl)-6- methyl-benzofuran-Z-cairboxylic acid, 2,3-dihydro-5- (2-methylene-butyryl)-6-fluoro-benzofuran-2- carboxylic acid, 2,3-dihydro-5-(2-methylene-butyryl)- 6,7-dimethyl-benzofuran-2-carboxylic acid and 2,3- dihydro-S-(2-methylene-propionyl)-6-methylbenzofuran-2-carboxylic acid.

The toxicity of the compounds of formula I on oral administration is of favourably low order.

The new compounds of formula I and their pharmaceutically acceptable salts with bases are thus suitable as medicaments which are preferably administered orally.

The pharmaceutically acceptable salts of the compounds of the invention may be prepared by any of the methods known in the art. To form the salts, it is possible to use inorganic or organic bases, such as, e.g. alkali or alkaline-earth metal hydroxides, carbonates or bicarbonates, triethanolamine or choline.

The daily dosages vary between 0.05 5 mg/kg for warm blooded animals. Suitable dosage units such as dragees or tablets, preferably contain 5-100 mg of an active substance, according to the invention, i.e. to 90 percent of a compound of the general formula I. They are produced by combining the active substance, e.g. with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for distinguising between varying dosages of active substance. Other suitable dosage units for oral administration are hard gelatine capsules as well as soft, closed capsules made of gelatine and a softener such as glycerin. The hard capsules preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers, such as sodium metabisulfite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, whereby stabilisers can likewise be added. In accordance with the foregoing, the present invention also provides a therapeutic composition consisting essentially of (1) a compound of formula I or a pharmaceutically acceptable salt thereof with a base and (2) a pharmaceutical carrier therefor.

Further the invention provides a method for producing a simultaneous diuretic and saluretic effect in mammals which method comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof with a base.

The following examples will serve to further typify the nature of the present invention, but should not be construed as a limitation on the scope thereof. All the temperatures are given in degrees centrigrade.

EXAMPLE I a. 20.0 g of 2,3-dihydro-5-butyryl-6-methylbenzofuran-2-carboxylic acid are refluxed, while stirring, with 4.1 g of paraformaldehyde and 8.2 g of dimethylamine hydrochloride in ml of dioxane for eight hours. The reaction mixture is then concentrated by evaporation in vacuo. To the obtained crude 2,3- dihydro-S-(2-dimethylaminomethyl butyryl)-6- methylbenzofuran-Z-carboxylic acid are added 21.0 g of anhydrous sodium acetate and 200 ml of glacial acetic acid. The obtained mixture is refluxed for two hours, while stirring, and is then concentrated by evaporation in vacuo. The residue is stirred into 100 ml of water, the obtained suspension adjusted to pH 2 with concentrated hydrochloric acid and stirred for one hour at 20. The organic acid is extracted with, three times ml of ether. The ether solution is dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from cyclohexane and xylene/- hexane, whereupon the 2,3-dihydro-5-(2-methylene butyryl)-6-methylbenzofuran-2-carboxylic acid melts at l00l02 The 2,3-dihydro-5-butyryl-6-methylbenzofuran-2- carboxylic acid, used as starting material, is produced as follows:

b. 35.0 g of 6-methylbenzofuran-2-carboxylic acid [cp. K. von Auwers, Ann.Chem. 408, 255 (1915)] are dissolved in 500 ml of a saturated, aqueous sodium hydrogen carbonate solution, and the solution cooled in an ice bath to 5. 500.0 g of 5 percent sodium amalgam are added, the reaction mixture is taken out of the ice bath after two hours and is allowed to stand for 24 hours at 20. The solution is then separated from the mercury, filtered and the filtrate adjusted to pH 1 with concentrated hydrochloric acid. The obtained precipitate is filtered off, washed with 300 ml of water and dried. The obtained 2,3-dihydro-6-methylbenzofuran- 2-carboxylic acid melts at 157 and, after recrystallisation from methanol/water, it melts at 158.

c. 25.2 g of the carboxylic acid obtained according to b), are slurried with 135 ml of nitrobenzene and, while stirring and cooling, 69.5 g of aluminum chloride are added in portions within 30 minutes, so that the temperature does not exceed At the same temperature, 22.3 g of butyryl chloride are added dropwise within 30 minutes. The reaction mixture is then further stirred for five hours in the ice bath, allowed to stand for 16 hours at room temperature, heated for a further hour to 40 and then poured on to 500.0 g of ice. 50 ml of concentrated hydrochloric acid are added to the obtained suspension. After the aluminum chloride has decomposed, the reaction mixture is extracted with, three times, 150 ml of ether. The ether extract is dried over sodium sulfate and concentrated by evaporation. The residue is slurried in hexane, shaken up, again separated from the hexane and recrystallised from benzene. The obtained 2,3-dihydro-5-butyryl-6-methylbenzofuran-Z-carboxylic acid melts at 140141.

EXAMPLE 2 a. Starting with the 2,3-dihydro-5-butyryl-7- chlorobenzofuran-2-carboxylic acid with paraformaldehyde and dimethylamine hydrochloride is obtained, analogously to example 1 a), the crude 2,3-dihydro-5- (Z-dimethyl-aminomethyl butyryl)-7- chlorobenzofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2,3-dihydro-5-(2-methylene butyryl)- 7-chlorobenzofuran-2-carboxylic acid, M.P. 144 (from benzene).

The starting material, the 2,3-dihydro-5-butyryl-7- chlorobenzofuran-2-carboxylic acid, is produced as follows:

b. 1 12.0 g of 2-allyl-6-chlorophenol [cp. D.S. Tarbell and J.W. Wilson, J.Am.Chem.Soc. 64, 1066 (1942)] are added, while stirring and within 30 minutes, to a carefully cooled mixture of 6.5 g of anhydrous sodium acetate and 160.0 g of 40 percent peracetic acid. The reaction temperature must not exceed l5-20 during 24 hours. An excess of aqueous, saturated sodium hydrogen carbonate solution is subsequently added. The etheral solution is washed with saturated, aqueous sodium hydrogen carbonate, sodium chloride and iron (ID-sulfate solution, so that the entire excess of peracetic acid is decomposed. (The excess peracetic acid is detected with potassium iodide in water.) The ether solution is then dried over sodium sulfate and concentrated by evaporation. The residue, the crude 6-chloro- 2-(2,3-epoxypropyl)-phenol, is heated for minutes to 110 and the reaction mixture distilled under high vacuum. The obtained 2,3-dihydro-2-hydroxymethyl- 7-chlorobenzofuran boils at 101108/0.02 Torr.

c. 15.0 g of 2,3-dihydro-2-hydroxymethyl-7- chlorobenzofuran are slurried in 120 ml of 4N sodium hydroxide solution by vigorous shaking, and cooled to 5. A solution of 72.0 g of potassium permanganate in 1.3 litres of water is added, all at once, to the suspension and the latter, while cooling, is shaken energetically, so that the temperature does not exceed After the reaction mixture is decolourised, it is filtered off from the manganese dioxide and this is washed with 300 ml of hot water. The cooled solution is adjusted to pH 1 with concentrated hydrochloric acid and then extracted with, three times, 500 ml of ether. The ether solution is dried over sodium sulfate and concentrated by evaporation. The residue is recyrstallised from carbon tetrachloride/benzene, whereupon the 2,3-dihydro-7- chlorobenzofuran-2-carboxylic acid melts at l45l46.

d. The carboxylic acid obtained according to c), is acylated, analogously to example 1 c), with butyryl chloride to the 2,3-dihydro-5-butyryl-7- chlorobenzofuran-2-carboxylic acid, M.P. 161 (from benzene).

EXAMPLE 3 From 2,3-dihydro-5-butyrylbenzofuran-2-carboxylic acid with paraformaldehyde and dimethylamine hydrochloride is obtained, analogously to example 1 a), the crude 2,3-dihydro-5-(2-dimethylaminomethyl butyryl)- benzofuran-Z-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2,3-dihydro-5-(2-methylene butyryl)- benzofuran-2-carboxylic acid, M.P. 97.5 (from carbon tetrachloride).

The starting material; the 2,3-dihydro-5-butyrylbenzofuran-Z-carboxylic acid, M.P. 133 (from acetic acid ethyl ester), is produced, analogously to example 1 c), from 2,3-dihydrobenzofuran-2-carboxylic acid [cp. R. Fittig and G. Ebert, Ann.Chem. 216, 166 (1883)] and butyryl chloride in the presence of aluminum chloride in nitrobenzene.

EXAMPLE 4 acid,

EXAMPLE 5 From 2,3-dihydro-5-butyryl-6-chlorobenzofuran-2- carboxylic acid with paraformaldehyde and dimethylamine-hydrochloride is produced, analogously to example l a), the crude 2,3-dihydro-5-(2- dimethylaminomethyl butyryl)-6-chlorobenzofuran-2- carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2,3-dihydro-5-(2-methylene butyryl)-6- chlorobenzofuran-2-carboxylic acid, M.P. (from benzene).

The starting material, the 2,3-dihydro-5-butyryl-6- chlorobenzofuran-2-carboxylic acid, is produced as follows:

Analogously to example 2 b), the mixture of 2-al1y1- 3-chlorophenol and 2-allyl-5-chlorophenol [cp. W.N. white, C.D. Slater, J.Org. Chem. 26, 3631 (1961) is converted into the mixture of 2,3-dihydro-2- 9 W hydroxymethyl-4-chlorobenzofuran and 2,3-dihydro-2- ml of concentrated hydrochloric acid added and the rehydroxymethyl-fi-chlorobenzofuran, which distills at suiting solution extracted with ether. The ether solution 95-l15/0.02 Torr. The distillate is separated by eluwas extracted with sodium hydrogen carbonate. This tion chromatography through silica gel with acetic acid aqueous solution was acidified to a pH of 1 with hydroethyl ester/benzene (3:100) as the elution agent. 5 chloric acid and then extracted with ether. After evap- The isolated 2,3-dihydro-2-hydroxymethyl-- orating the ether and purifying through a chromatograchlorobenzofuran is then oxidised, analogously to exphy column 2,3-dihydro-5-(Z-methylene-butyryl)-6- a p 2 t0 the 2, y hl r nz f r n-2- methyl-benzofuran-2-carboxylic acid was obtained. carboxylic acid, M.P. 163 (from benzene), which is MP. l00-l04. acylated, analogously to example 1 c) with butyryl l0 EXAMPLE 20 chloride to the 2,3-dihydro-5-butyryl-6- chlorobenzofuran-Z-carboxylic acid, M.P. 110 (from benzene).

Analogously to Example 19 2,3-dihydro-6-methylbenzofuran-Z-carboxylic acid was acylated to produce 2,3-dihydro-5-(2-methyl-acrylyl)-6-methyl- EXAMPLES 6-18 benzofuran-Z-carboxylic acid, M.P. l00-102, with nltrobenzene, aluminum chloride and methylacryhc Analogously to Example 1a starting from the correacid anhydride (c.f. Brotherton, J.Sm1th, Jr. and J.W. sponding 5-alkanoyl-benzofuran (or benzoth1ophene)- y g Chem 26 12834) 2-carboxylic acids are obtained the following 5-(2- methylene-alkanoyl)-benzofuran (orbenzothiopheney EXAMPLE 21 Z-carboxylic acids of formula I: a. 8.7 g of 2,3-dihydro-5-(2-bromo-2-bromomethyl- TABLE 1 Example R k 11 Z: Y1 Y: M.l. ()rystalliscd from O H CH3- (6) H 11 124 Benzene. 0 C113 (6) CH3 (7) H H 102-104 0614. 0 H C!-I3 (6) H H Heptano. O H C113" (6) H H 115-116 Acetic acid ester. 0 H C113- (6) CH3- H Amorphous O H F- 86) H H 113 Cyclohexane/benzene. 0 H CH1 H2 (6) H H -101 D0. 0 H CH3- (6) H H 70-80 Heptane. 0 Cl- (0) CH3- (7) H H 152-153 C014. S C1 (4) H H H 155 Nitromethane. S (6) H H H Acetic acid ester. S OCH;CH; (6) H H H 118 Nitromethane. O a- H H H 72 Hexane.

The corresponding S-alkanoyl compound of formula 35 butyryl)-6-methyl-benzofuran-Z-carboxylic acid were IVb used as starting materials are prepared analogously refluxed for 10 minutes with 20 g of potassium iodide to Example 1c by the Friedel-Craft acylation: v in 100 ml of ethanol and cooled. After cooling the mix- TABLE II R X Z; Z: Y1 Y2 MP. Crystallised from CH1 O H C1I3 (6) H H Cyclohexanv/acetic acid ester. CHJCHP 0 CH3--- (6) C11;- (7) 11 H 148 Aeeticacid ester. CH3(CIl:');. O 11 Cli (6) H II 137 ()yclohvxanv/utwtic acid vstvr.

CH;\ 0 H CII;- s H H 132 Benzene.

CHaCH2 0 H CH3 (6) CH H 98-100 D0. CHaCHr- 0 II F 6) H H 144 Cyclohexane/acetic acid ester. CH3CH2 0 H CH3 H 6 H H 83 con. CH3 CH2 J O H CHa- (6) H H 137 Cyclohexane/acetic acid ester.

aCH 0 C1 (6) CH;- (7) H H 151 Cyelohexane. CHsCH s Cl- 4 H H H 178 Methanol. CHaCHz- S H CH3- (6) H H 158 Cyclohexane. CHaCH;-. s H cH cmo- (6) H H 144 Benzene. CHKCHm 0 H CH3 6 H H 136 D0.

EXAMPLE 19 ture was mixed with excess aqueous sodium thiosulfate 25 2 g of 2 3 dihydro 6 methy| benzofuran 2 solution, then acidified with hydrochloric acid and excarboxylic acid were mixed with ml of nitrobeng ether sohmon w evaporated zene and 69.5 g of aluminum chloride was added in 0 2 er vacuumhan t e resldglgwasdpunfied by column portions over a period of 30 minutes with stirring and mmftograp h 'l b f z g 'f f g cooling so that the temperature did not arise above 10". 83 2 g' 1 oxy acld' At the same temperature 25 g of Z-Methylenebutyryl was 0 mm chloride was added dropwise to the reaction mixture. 1). The starting material was prepared as follows: 25,2 The reaction mixture was then stirred for 5 hours in an 65 g of 2,3-dihydr0-6-methyl-benzofuran-2-carboxylic ice bath and for a further 16 hours at room temperaacid in 135 ml of nitrobenzene was acylated to 2,3-

ture. The mixture was then poured into 500 g of ice, 50 dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6- methyl-benzofuran-Z-carboxylic acid with 59 g of 2-Bromo-2-bromomethyl-butyryl chloride in the presence of 169.5 g of aluminum chloride.

EXAMPLE 22 10 g of 2,3-Dihydro--(2-bromo-2-bromomethylbutyryl)-6-methyl-benzofuran-2-carboxylic acid was boiled under reflux for 1 hour with 3 g of zinc dust in 100 ml of ethanol and the resulting solution filtered and concentrated. The 2,3-dihydro-5-(Z-methylenebutyryl)-o-methyl-benzofuran-Z-carboxylic acid obtained, MP. 100-l02, was purified by column chromatography. Analogously, 2,3-dihydro-5-(2-bromo-2- bromomethyl-valeroyl)-6-methyl-benzofuran-2- carboxylic acid, M.P. 179 (from benzene) was prepared similarly 2,3-dihydro-5-(2-bromo-2- bromomethyl-hexanoyl)-6-methyl-benzofuran-2- carboxylic acid, M.P. 146, from benzene.

EXAMPLE 23 20 g of 2,3-dihydro-5-butyryl-6-methyl-benzofuran- 2-carboxylic acid was boiled under reflux for 8 hours with 4.1 g of paraformaldehyde and 12.5 g of morpholine chlorohydrate in 125 ml of dioxane. The reaction mixture was then concentrated in vacuo and to the raw 2,3-dihydro-5-(2-morpholino-methyl-butyryl)-6- methyl-benzofuran-Z-carboxylic acid obtained 21 g of water free sodium acetate and 200 ml of glacial acetic acid was added. The resulting mixture was boiled under reflux and with stirring for two hours and evaporated in vacuo. The residue was stirred with 100 ml of water. The resulting suspension was acidified with concentrated hydrochloric acid to a pH of 2 and stirred for one hour at 20. The organic acid was extracted with three times 150 ml of ether. The ether solution was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallised from cyclohexane and xylenehexane to give 2,3-dihydro-5-(2-methylene-butyryl)-6- methyl-henzofuran-Z-carboxylic acid melting at 100-l02 EXAMPLE 24 20 g of 2,3-dihydro-5-butyryl-6-methyl-benzofuran- 2-carboxylic acid was boiled under reflux with stirring for 8 hours with 4.1 g of paraformaldehyde and 12 g of piperidine-chlorohydride in 125 ml of dioxane. The reaction mixture was then concentrated in vacuo and to the raw 2,3-dihydro-5-(2-piperidino-methyl-butyryl)- 6-methyl-benzofuran-carboxylic acid 21 g of water free sodium acetate and 200 ml of glacial acetic acid was added. The resulting mixture was boiled under reflux with stirring for two hours and evaporated in vacuo. The residue was stirred with 100 ml of water. The resulting suspension was acidified with concentrated hydrochloric acid to a pH of 2 and stirred for one hour at 20. The organic acid was extracted with three times 150 ml of ether. The ether solution was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallised from cyclohexane and xylene-hexane to give 2,3-dihydro-5-(2-methylene-butyryl)-6-methylbenzo-furan-Z-carboxylic acid melting at 100l02.

EXAMPLE 25 a. An amount of 22.2 g of 2,3-dihydro-5-valeryl-6,7- dimethylbenzofuran-2-carboxylic acid is refluxed with 4.1 g of paraformaldehyde and 8.2 g of dimethylamine hydrochloride in ml of dioxane for 8 hours while stirring is maintained. The reaction mixture is then concentrated in vacuo. To the obtained crude 2,3-dihydro- 5-(2-dimethylaminomethyl-valeryl)-6,7-dimethylbenzofuran-Z-carboxylic acid hydrochloride are added 21 g of anhydrous sodium acetate and 200 ml of glacial acetic acid. The obtained mixture is refluxed, with stirring, for two hours, and is then concentrated in vacuo. The residue is mixed by stirring with 100 ml of water; the obtained suspension is adjusted with concentrated hydrochloric acid to pH 2, and stirred for one hour at 20. The organic acid is extracted by the suspension being shaken out three times with 150 ml of ether. The ether solution is dried over sodium sulphate, and concentrated by evaporation. The residue is recrystallised from heptane, whereupon the 2,3-dihydro-5-(2- methylene-valeryl)-6,7-dimethylbenzofuran-2 -carboxylic acid melts at 82.

The starting material is produced as follows:

b. 45 g of 2,3-dimethylphenol and 50 g of malic acid are ground to powder, and well mixed together; to the mixture are added 100 ml of concentrated sulphuric acid, and the whole slowly heated, with stirring, so that the reaction temperature after 30 minutes is The solution is maintained for a further 30 minutes at this temperature; it is then poured on to one kg of ice, and the formed suspension stirred for 30 minutes. The precipitated crystals are filtered off under suction, and recrystallized from ethanol. In this manner is obtained 7,8-dimethyl-coumarin, M.P. 128-130; yield 36.3 g.

c. An amount of 34.8 of the coumarin obtained according to b) is dissolved in 60 ml of chloroform. To this solution is added dropwise a solution of 32.5 g of bromine in 20 ml of chloroform, with stirring and occasional cooling with ice, so that the reaction temperature is 2025. The mixture is stirred for a further 20 minutes at room temperature, and the chloroform is subsequently completely evaporated off in vacuo. The residue is added portionwise to a mixture of 90 g of potassium hydroxide with 300 ml of ethanol, the reaction temperature being maintained by ice cooling between 30 and 40. The mixture is subsequently stirred for 30 minutes at 40 and for 30 minutes at 80; it is then poured on to two litres of ice water. The aqueous alkaline solution is washed twice with 400 ml of ether each time, and the H-value adjusted to 2-3 with cone. hydrochloric acid. The obtained suspension is stirred for half an hour at room temperature. The precipitated crystals are filtered off under suction, and recrystallised from ethanol. In this manner is obtained 6,7- dimethylbenzofuran-2-carboxylic acid, M.P. 237-239.

d. An amount of 35 g of the acid obtained according to c) is dissolved in 500 ml of a saturated aqueous sodium hydrogen carbonate solution, and the solution cooled in an ice bath to 5. To the solution are added 500 g of 5 percent sodium amalgam, the reaction mixture is removed after two hours from the ice bath, and is allowed to stand for 24 hours at 20. The solution is subsequently separated from from the mercury, filtered, and the filtrate adjusted with concentrated hydrochloric acid to pH 1. The formed precipitate is filtered off, washed with 300 ml of water, and dried. The obtained 2,3-dihydro-6,7-dimethylbenzofuran-2- carboxylic acid melts at 182 (from ethanol).

e. To 27.2 g of the carboxylic acid obtained according to d) are added ml of nitrobenzene; to the mixture are added portionwise in the course of 30 minutes, with stirring and cooling, 69.5 g of aluminium chloride, so that the temperature does not exceed 10. At the same temperature are added dropwise, within 30 minutes, 25.3 g of valeryl chloride. The reaction mixture is then further stirred for five hours in an ice bath; it is afterwards allowed to stand for 16 hours at room temperature. heated for a further hour to 40, and then poured on to 500 g of ice. To the obtained suspension are added 50 ml of concentrated hydrochloric acid. After the aluminium chloride complex has decomposed, the reaction mixture is extracted three times with 150 ml of ether each time. The ether extract is dried over sodium sulphate, and concentrated by evaporation. The residue is suspended in hexane, shaken up, separated from the hexane, and recrystallised from ethyl acetate/- hexane. The obtained 2,3-dihydro-5-valefyl-6,7- dimethylbenzofuran-Z-carboxylic acid melts at l28-129.

EXAMPLE 26 1000 g of 2,3-dihydro-5-(2-methylene-butyryl)-6- methylbenzofuran-Z-carboxylic acid are mixed with 550 g of lactose and 292 g of potato starch. The mixture is moistened with an aqueous solution of 8 g of gelatine and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talcum, 10 g of magnesium stearate and 20 g of colloidal silicon dioxide are mixed in. The mixture is pressed into 10,000 tablets each weighing 200 mg and each containing 100 mg of active substance. Optionally, the tablets can be provided with grooves for a more accurate adjustment of the dosage amount.

EXAMPLE 27 A granulate is produced from 1000 g of 2,3-dihydro- 5 (Z-methyIene-butyryl)-6-methylbenzofuran-2- carboxylic acid, 379 g of lactose and the aqueous solution of 6 g of gelatine. After drying, the granulate is mixed with 10 g of colloidal silicon dioxide, 40 g of talcum, 60 g of potato starch and 5 g of magnesium stearate and the mixture pressed into 10,000 dragee cores. These are subsequently coated with a concentrated syrup made from 533.5g of crystallised saccharose, 20 g of shellac, 75 g of gum arabic, 250 g of talcum, 20 g of colloidal silicon dioxide and 1.5 g of dyestuff, and dried. The obtained dragees each weigh 240 mg and each contain 100 mg of active substance.

EXAMPLE 28 To produce 1000 capsules each containing 100 mg of active substance, 100 g of 2,3-dihydro-5-(Z-methylenebutyryl)-6-methylbenzofuran-2-carboxylic acid are mixed with 9.5 g of talcum and 0.5 g of magnesium stearate and the mixture is put through a sieve (e.g. Sieve IV, Ph. Helv. V). Capsules of size are then uniformly filled from the mixture.

EXAMPLE 29 Tablets capsules and dragees were prepared according to examples 26 to 28 using the same quantities of the following compounds as active ingredient.

a. 2,3-dihydro--(Z-methylene-butyryl)6-chloro-7- wherein R is alkyl having at most six carbon atoms,

Y, and Y, are hydrogen or methyl,- and Z, and Z are hydrogen, chloro, fluoro, bromo, methyl, ethyl, methoxy or ethoxy as well as the pharmaceutically acceptable salts thereof with bases.

2. A compound as defined in claim 1 wherein R is alkyl having at most 6 carbon atoms,

Y, and Y are hydrogen,

Z, is hydrogen or methyl and Z is methyl, chloro or fluoro,

as well as the pharmaceutically acceptable salts thereof with bases.

3. A compound as defined in claim 1 which is 2,3- dihydro-5-(2-methylene-butyryl)-6-methylbenzofuran-Z-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.

4. A compound as defined in claim 1 which is 2,3- dihydro-S-(2-methylene-butyryl)-6-chlorobenzofuran-Z-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.

5. A compound as defined in claim 1 which is 2,3- dihydro-5-(2-methylene-3-methyl-butyryl)-6-methylbenzofuran-Z-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.

6. A compound as defined in claim 1 which is 2,3-

-dihydro-5 Z-methyIene-butyryl)-6-fluoro-benzofurancally acceptable salts thereof with bases. 

2. A compound as defined in claim 1 wherein R is alkyl having at most 6 carbon atoms, Y1 and Y2 are hydrogen, Z1 is hydrogen or methyl and Z2 is methyl, chloro or fluoro, as well as the pharmaceutically acceptable salts thereof with bases.
 3. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 4. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-benzofuran-2-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 5. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-3-methyl-butyryl)-6-methyl-benzofuran-2 -carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 6. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-butyryl)-6-fluoro-benzofuran-2-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 7. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-butyryl)-6,7-dimethyl-benzofuran-2-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 8. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-propionyl)-6-methyl-benzofuran-2-carboxylic acid as well as the pharmaceutically acceptable salts thereof with bases.
 9. A compound as defined in claim 1 which is 2,3-dihydro-5-(2-methylene-valeryl)-6,7-dimethyl-benzofuran-2-carboxylic as well as the pharmaceutically acceptable salts thereof with bases. 